New Hypertension Drug Delivers "Surprising" Long-Term Effects Despite Mixed Trial Results

Researchers at the American College of Cardiology’s Annual Scientific Session (ACC.26) have unveiled data from the KARDINAL trial, a phase 2 study of the investigational drug tonlamarsen (Kardigan). The results present a scientific paradox: while the drug successfully achieved a massive reduction in a key blood-pressure-regulating protein, it did not show an additional blood pressure benefit when administered monthly compared to a single initial dose.¹

A New Approach to a Global Problem

Hypertension remains a global health crisis, with approximately half of US adults living with uncontrolled high blood pressure. For many, the challenge lies in pill burden—the need to take multiple daily medications, which often leads to poor adherence.²

Tonlamarsen represents a cutting-edge class of antisense oligonucleotide therapies. Unlike traditional pills that must be taken daily, this injectable drug targets the liver to suppress the production of angiotensinogen (AGT), the primary "building block" of the renin-angiotensin-aldosterone system (RAAS) that regulates blood pressure. By silencing the gene responsible for AGT, researchers hoped to provide a stable, long-acting solution for patients who remain hypertensive despite taking 2 to 5 other medications.¹

The KARDINAL Trial Design

The trial enrolled 206 participants across 39 US sites, with an average age of 61 and a baseline systolic blood pressure of approximately 147 mmHg. Notably, nearly half of the participants were Black, a population often disproportionately affected by hypertension.¹

The study utilized a unique design: after a placebo lead-in, all participants received a single 90 mg dose of tonlamarsen. Four weeks later, they were randomized to either continue receiving monthly tonlamarsen injections or switch to a placebo for the remainder of the 20-week study.¹

Mixed Results: The Data Gap

The study met one of its coprimary end points with flying colors: plasma AGT levels. By week 20, those receiving monthly tonlamarsen saw their AGT levels plummet by 67.2%, while those who switched to placebo saw a much smaller reduction of 23%.¹

However, the second primary end point—office systolic blood pressure—produced a surprising result. Both groups experienced an identical 6.7 mmHg drop in blood pressure. Essentially, the group that stopped the drug after 1 dose maintained the same blood pressure improvement as the group that continued the medication for 5 months.¹

"More Questions Than Answers"

"The continued decrease in blood pressure after a single dose surprised us," said Luke Laffin, MD, a cardiologist at Cleveland Clinic and the study’s lead author. "We also did not anticipate the finding that the percentage of angiotensinogen reduction didn’t necessarily correspond to blood pressure lowering 20 weeks out."¹

The drug has an elimination half-life of only 2 to 4 weeks, meaning it should have been largely gone from the system of the single-dose group by the end of the study. Yet, their AGT levels remained suppressed by 23% even 20 weeks after that solitary injection.¹

Researchers have proposed several theories for this "carryover effect":

1. Sustained Benefit: A single dose may trigger a 6 mmHg to 7 mmHg drop that is maintained by the body even as AGT levels slowly begin to recover, a phenomenon known as RAAS hysteresis.
2. Sufficient Suppression: The 23% AGT suppression seen in the placebo group might have been enough to maintain the full blood pressure benefit, meaning the extra 44% reduction from monthly dosing provided no incremental gain.
3. Resistance: It is also possible that for patients already on multiple medications, there is a "floor" to how much the RAAS system can be further suppressed to lower blood pressure.

Safety and Future Directions

From a safety perspective, tonlamarsen was generally well-tolerated. The most frequent adverse effect was injection site reactions, occurring in 19% of those receiving monthly doses compared to 3% in the single-dose group. Other serious adverse events were infrequent and similar between the two groups. One death occurred during the study, but it was deemed unrelated to the drug.¹

While the KARDINAL trial may not have shown a benefit for monthly dosing over a single dose in this specific population, it has opened new doors. Laffin noted that future research might focus on acute severe hypertension, where a single, long-acting injection could stabilize a patient’s blood pressure post-discharge without relying on daily pill adherence.¹

The findings emphasize that when it comes to the complex machinery of human blood pressure, more drug is not always better—but a little might go a much longer way than previously thought.

REFERENCES

1. Investigational drug delivers mixed results for uncontrolled blood pressure. News release. American College of Cardiology. March 28, 2026. Accessed March 28, 2026. https://www.acc.org/Latest-in-Cardiology/Articles/2026/03/25/21/27/sat-345pm-kardinal-acc-2026

2. Laffin LJ, Wang Q, Sarraju A, et al. Efficacy of tonlamarsen in patients with uncontrolled hypertension: the KARDINAL phase 2 randomized clinical trial. J Am Col Cardiol. 2026. doi:10.1016/j.jacc.2026.03.034